Methodology gaps in Medicine

Representative open questions

Showing 30 of 794 — one per source paper, highest-quality first.

• Gut microbiota in chronic kidney disease-mineral and bone disorder: shared mechanisms, disease-specific signatures, and therapeutic prospects (2026) · doi

  There is a need for standardized strain selection methods in microbiota interventions for CKD-MBD, with specific focus on the Erysipelotrichaceae and Clostridium sensu stricto taxa.

• Heart-brain axis pathophysiological understanding and clinical impact (2026) · doi

  The molecular imaging techniques used to investigate the brain-heart axis and cardiac dysfunction after cerebral ischemia (reference 113) have not been systematically compared across different imaging modalities or validated in longitudinal cohorts to establish standardized protocols for clinical implementation.

• CUIDADO TRANSICIONAL HOSPITAL-DOMICÍLIO REALIZADO POR ENFERMEIRAS A PESSOAS IDOSAS COM MARCAPASSO ARTIFICIAL: PROTOCOLO DE REVISÃO DE ESCOPO (2026) · doi

  The scoping review protocol does not specify a critical quality assessment methodology for evaluating the methodological quality of included studies on transitional hospital-to-home nursing care for elderly patients with artificial pacemakers. While the authors mention that quality evaluation will not be performed per JBI guidelines for scoping reviews, potential methodological limitations in the primary studies will only be described in the synthesis without formal assessment tools.

• Multifunctional Lipid Polymer Hybrid Nanocarriers in Cancer Therapy: Recent Developments and Challenges (2026) · doi

  Different RU-loaded LPH NP formulations exhibited distinct tissue distribution patterns (TPGS-LPH Fr=1.13 liver, Solutol-LPH Fr=0.94 liver, Tween-LPH Fr=2.26 liver), but the relationship between surfactant composition and organ-specific biodistribution in spleen and kidney has not been mechanistically characterized.

• The impact of traumatic injury on the respiratory system; a narrative review of injury-associated and clinically-induced mechanisms of trauma-associated pneumonia (2026) · doi

  The brain-lung axis has been identified as a potential contributor to trauma-associated pneumonia following isolated brain injury, but the specific neuroimmune pathways linking acute brain trauma to altered respiratory immune function and pneumonia development have not been systematically characterized in clinical cohorts.

• FDG-PET/CT based small volume accelerated immuno chemoradiotherapy in locally advanced NSCLC (PACCELIO) – a randomized, open-label, multicenter phase II trial protocol (2026) · doi

  The trial prospectively evaluates immunomarkers (NLR, ALI) and immune-related radiotherapy planning parameters (EDIC, PET-related imaging parameters) in NSCLC, but the specific mechanistic relationships between these biomarkers and response to hypofractionated, accelerated chemoradiotherapy combined with consolidative immunotherapy have not been established. The longitudinal kinetics of these immunomarkers during the condensed treatment schedule require quantitative correlation analysis with clinical outcomes.

• Impact of Health Education and Preventive Interventions on Non- Communicable Diseases in Rural Communities: A Community-Based Randomized Controlled Trial (2026) · doi

  The study found that blood glucose levels remained unchanged in the control group despite standard medical treatment, suggesting that existing diabetes management protocols do not effectively regulate metabolic conditions in patients with combined hypertension, diabetes, and obesity. Future research should investigate which specific pharmacological and behavioral interventions are most effective for glycemic control in this triple-comorbidity population.

• Proteogenomic decoding of chemotherapy resistance in patients with triple-negative breast cancer (2026) · doi

  The NMF clustering approach selected k=5 clusters based on cophenetic correlation coefficients, dispersion, and consensus stability metrics, but the paper does not evaluate whether alternative clustering algorithms (hierarchical clustering, k-means, or graph-based methods) would yield different proteogenomic subtypes or affect the identification of chemotherapy resistance signatures in triple-negative breast cancer.

• Activation of anti-inflammatory pathways by polyunsaturated fatty acid signaling may protect neurodevelopment in children prenatally exposed to methylmercury (2026) · doi

  The use of different donors for placenta and cord blood samples prevented direct comparison between tissue types and limited conclusions about prenatal mercury exposure dynamics. Future investigations should employ paired fetal-maternal tissue samples (placenta and cord blood from the same individual) to enable direct assessment of oxylipin metabolite patterns across compartments and establish temporal relationships in mercury exposure.

• Neurosurgery as an immune anchor point: a translational framework for perioperative immunoengineering (2026) · doi

  The paper proposes neurosurgery as an immune anchor point for perioperative immunoengineering but lacks specific protocols for timing and dosing of immunotherapeutic interventions relative to surgical resection in different neurosurgical contexts (brain tumors vs. hemorrhagic stroke vs. aneurysmal subarachnoid hemorrhage). Quantitative frameworks are needed to characterize how surgical trauma window affects meningeal lymphatic function and glymphatic clearance in distinct pathological settings.

• Autologous Platelet Concentrates in Sports Medicine: Mechanisms of Tissue Regeneration and Clinical Applications – A Narrative Review (2026) · doi

  Studies examining hamstring injuries with autologous platelet concentrates lack standardized return-to-play criteria, consistent rehabilitation intensity protocols, and uniform PRP composition specifications, preventing meaningful outcome comparison and development of generalizable treatment algorithms for acute muscle strain management.

• What is The Effect of Early Enteral Nutrition on Mortality in Critically Ill Patients Receiving Vasopressor Support? : A Systematic Review (2026) · doi

  The paper identifies a critical need to develop and validate biomarkers of gut perfusion and tolerance (such as lactate trends, base deficit measurements, and splanchnic perfusion indicators) that can guide individualized early enteral nutrition strategies in vasopressor-supported patients, but no studies have prospectively evaluated which combination of biomarkers best predicts feeding tolerance and prevents bowel ischemia.

• Decision-ready evidence for vital pulp therapy: a network meta-analysis of bioactive materials in mature permanent teeth (2026) · doi

  Moderator variables critical to vital pulp therapy outcomes—specifically hemostasis regimen/duration, timing of same-visit restoration placement, and isolation breach frequency—were inconsistently reported across included studies, preventing robust meta-regression analysis. Future RCTs in pulpotomy and direct pulp capping should prospectively document and stratify these operative factors to quantify their independent contribution to success rates.

• Exercise benefits in metabolism on cardiovascular disease (2026) · doi

  The effects of different types of structured exercise sessions (moderate-intensity, high-intensity, and resistance exercise) on glucose control have been examined in type 1 diabetes patients, but the acute glycemic effects in real-world settings need further characterization across different exercise modalities, intensities, and durations to establish personalized exercise prescription guidelines for cardiovascular disease prevention.

• What is the diagnostic accuracy of different clinical diagnostic criteria (Rotterdam, NIH, and Androgen Excess Society) for identifying polycystic ovary syndrome in women of reproductive age? : A Systematic Review (2026) · doi

  Age-related decline in ovarian volume documented by Alsamarai et al. over 7-15 years of follow-up necessitates development of age-stratified diagnostic thresholds for PCOS ultrasonographic criteria, particularly for women aged 35-40 years, but no age-based adjustment models have been established across the Rotterdam, NIH, or Androgen Excess Society diagnostic frameworks.

• Insights into nuciferine: A natural multifunctional bioactive alkaloid (Review) (2026) · doi

  Biomarker-guided clinical trial designs for nuciferine stratification in patient populations have not been developed; adaptive trial designs to optimize dosing, treatment duration, and endpoint assessment based on interim results remain unspecified.

• Deep learning-based multimodal prediction of chronic kidney disease stage (2026) · doi

  The paper identifies that early-stage CKD patients (G1 and G2) show high similarity across clinical indicators and require subtle distinction of nonlinear characteristic differences. However, the specific feature-level or decision-level fusion mechanisms that enable the multimodal model to capture these fine-grained differences between G1 and G2 stages are not explicitly analyzed or ablated.

• Effectiveness of screening modalities for early detection of diabetic retinopathy: a systematic review and meta-analysis of tele-ophthalmology, AI-based tools, and conventional methods (2026) · doi

  Symptomatic indicators (e.g., vision complaints, ocular symptoms) have been systematically excluded from DR screening modality evaluations; comparative effectiveness of AI-based tools and conventional methods that incorporate symptomatic data versus fundus imaging alone needs investigation.

• The Relationship between a History of Cesarean Section and The Incidence of Placenta Accreta : A Systematic Review (2026) · doi

  The dose-response relationship between multiple cesarean sections and placenta accreta risk has been established, but the specific influence of CS closure technique, suture material, infection status, and individual tissue healing characteristics on scar quality and subsequent PAS expression remains uninvestigated. Research directly comparing accreta incidence across different surgical closure methods in prospective cohorts is needed.

• A systematic review of sample size determination in Bayesian randomized clinical trials: full Bayesian methods are rarely used (2026) · doi

  The systematic review identifies that full Bayesian methods for sample size determination are rarely used in randomized clinical trials, yet the included studies predominantly employ hybrid approaches combining Bayesian and frequentist elements. There is a specific gap in understanding why practitioners avoid fully Bayesian sample size determination methods and what methodological barriers or computational challenges prevent their adoption in clinical trial design.

• Unveiling the relationship of the comorbidity between depression and type 2 diabetes mellitus: a macro analysis and micro interpretation (2026) · doi

  The bibliometric analysis was constrained by technical limitations preventing simultaneous analysis of multiple databases for depression and T2DM comorbidity research. Future investigations should develop integrated multi-database analysis protocols to capture a more comprehensive literature landscape and reduce the risk of overlooking outstanding papers in this field.

• Engineered exosome biomedical technologies for precision diagnosis and therapy in orthopedic diseases (2026) · doi

  Exosome isolation techniques (ultracentrifugation, density gradient separation, immunoaffinity capture, acoustic purification) have been compared in limited contexts; their relative efficacy and standardization for orthopedic-specific exosome populations (osteoblast-derived, osteoclast-derived exosomes) from clinical bone tissue samples remain unestablished.

• Immune molecular mechanisms of PANoptosis in sepsis-induced acute kidney injury (2026) · doi

  The role of neutrophil extracellular traps (NETs) in PANoptosis-mediated sepsis-induced acute kidney injury is mentioned but not thoroughly investigated; specific studies examining NET-induced NLRP3 inflammasome activation and caspase-11-mediated pyroptosis in renal tubular cells are needed.

• Science fiction and the futures of artificial womb technology: towards a carrier bag theory of design fiction (2026) · doi

  Items 6 and 11 identify obstacles to fetal development in AWT facilities—specifically psychological maturation without auditory stimulus from the gestating body and maternal-fetal bonding quality—but provide no experimental design or measurement framework to empirically assess how auditory deprivation or bonding interventions in ex utero gestation affect neurodevelopmental outcomes.

• Peran Tenaga Kesehatan dalam Penanganan Penyakit Degeneratif pada Lansia di Puskesmas Negeri Lama: Sebuah Studi Kasus (2026) · doi

  Mixed-methods research combining in-depth interviews with elderly patients and families alongside quantitative measurement of quality of life using WHOQOL-BREF or EQ-5D questionnaires and clinical outcomes (blood pressure, blood glucose) has not been conducted to capture both patient perspectives and objective health metrics in degenerative disease management at primary health centers.

• Evidence-based approaches for Empty Nose Syndrome management: a systematic review highlighting current treatments and future directions (2026) · doi

  Case series studies on Empty Nose Syndrome treatments lack standardized consecutive patient enrollment documentation and consistent follow-up duration (43.3% rated low risk, 20% high risk), preventing robust long-term outcome assessment beyond one year and limiting evaluation of treatment durability.

• Multimodal artificial intelligence in urologic precision oncology: from algorithm to translational medicine (a systemized narrative review) (2026) · doi

  While digital twins for personalized treatment in uro-oncology are proposed as emerging applications (reference 38), the specific methodology for integrating real-time patient genomic data, treatment response biomarkers, and imaging phenotypes into clinically actionable digital twin models for prostate cancer remains underdeveloped.

• Protocol for non-invasive assessment of skeletal muscle structure and function in adolescents with single ventricle heart disease: a cross-sectional, case-control study (2026) · doi

  The current study design is cross-sectional and prohibits identification of causality between skeletal muscle deficits and adverse outcomes in SV patients. Longitudinal studies tracking skeletal muscle structure and function changes over time in adolescents with single ventricle physiology are needed to establish causal relationships.

• A sham-controlled randomised trial evaluating the safety, acceptability, and efficacy of autonomic neuromodulation using transcutaneous vagal sensory stimulation in uncontrolled hypertensive patients: rationale and study design of the SCRATCH-HTN study (2026) · doi

  The study identifies transient side effects of transcutaneous auricular vagal stimulation (tAN) including light-headedness, fatigue, mood changes, and increased ventricular extrasystoles at <1% frequency, but does not specify the duration of these adverse events or long-term safety monitoring protocols required to characterize whether these effects truly diminish with sustained device usage.

• Medical clinical minds meet artificial intelligence: Italian physicians' knowledge, attitudes, and concordance between Italian physicians and AI-generated diagnoses. A national cross-sectional study (2026) · doi

  The non-probabilistic snowball sampling method does not guarantee representativeness across different medical specialities, geographic regions, and levels of physician seniority within the Italian healthcare system. Results cannot be fully generalised to the national population due to potential imbalances in these stratified demographic variables.